Interferon gene therapy reprograms the leukemia microenvironment inducing protective immunity to multiple tumor antigens

Nat Commun. 2018 Jul 24;9(1):2896. doi: 10.1038/s41467-018-05315-0.


Immunotherapy is emerging as a new pillar of cancer treatment with potential to cure. However, many patients still fail to respond to these therapies. Among the underlying factors, an immunosuppressive tumor microenvironment (TME) plays a major role. Here we show that monocyte-mediated gene delivery of IFNα inhibits leukemia in a mouse model. IFN gene therapy counteracts leukemia-induced expansion of immunosuppressive myeloid cells and imposes an immunostimulatory program to the TME, as shown by bulk and single-cell transcriptome analyses. This reprogramming promotes T-cell priming and effector function against multiple surrogate tumor-specific antigens, inhibiting leukemia growth in our experimental model. Durable responses are observed in a fraction of mice and are further increased combining gene therapy with checkpoint blockers. Furthermore, IFN gene therapy strongly enhances anti-tumor activity of adoptively transferred T cells engineered with tumor-specific TCR or CAR, overcoming suppressive signals in the leukemia TME. These findings warrant further investigations on the potential development of our gene therapy strategy towards clinical testing.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology*
  • Cell Line, Tumor
  • Cells, Cultured
  • Female
  • Gene Expression Regulation, Leukemic
  • Genetic Therapy / methods*
  • Immunity / genetics
  • Immunity / immunology*
  • Immunotherapy, Adoptive / methods
  • Interferons / genetics
  • Interferons / immunology*
  • Interferons / metabolism
  • Male
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / genetics
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / immunology*
  • Precursor Cell Lymphoblastic Leukemia-Lymphoma / therapy
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • Tumor Microenvironment / genetics
  • Tumor Microenvironment / immunology*


  • Antigens, Neoplasm
  • Interferons